Opioid-induced hyperalgesia—Pathophysiology and clinical relevance

(A) Hyperalgesia is characterised by a leftward shift of the stimulus–pain curve, i.e. a normally non-painful stimulus becomes subsequently noxious (=Allodynia), while a normally painful stimulus increases in intensity. (B) A rightward shift of the dose–effect curve can be observed for the tolerance development i.e. the drug loses its potency.

The ‘Opponent Process Theory’ demonstrates the function of an activated, positive process (a-Process) simultaneously with a compensatory (opposing) response, i.e. a negative process (b-Process). The opioid-induced analgesia and hyperalgesia are due to the interaction of the two opposing processes (a+b). A repeated exposure to opioids results in a decrease of analgesic effect via the increasing activation of pronociceptive systems (A), while a fairly long-term opioid therapy reduces the analgesic effect (B). Based on .

Schematic diagram of antinociceptive and pronociceptive mechanisms mediated by μ-agonists. For further information, see text.

(A) Time course of pain ratings during continuous electric stimulation in humans. The current was delivered by a stainless-steel needle which was inserted intradermally over a length of 1cm at the central volar forearm of the subjects. A skin surface electrode (1.0cm×0.5cm) was attached directly above the needle serving as anode. The infusion of remifentanil causes an initial, dose-dependent decrease in pain intensity. After completion of the infusion, a significant pain increase can be observed. (B) During the infusion of remifentanil, the observed antihyperalgesic effects are associated with a significant increase in the area of secondary mechanical hyperalgesia after completion of infusion. Shown are averages and standard error (n=13). Based on [129].